Focus : Comprehensive molecular portraits of human breast tumours

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

Source: Comprehensive molecular portraits of human breast tumours. The Cancer Genome Atlas Network; Genome sequencing centres: Washington University in St Louis, Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF, Fulton LL, Dooling DJ, Ding L, Mardis ER, Wilson RK; Genome characterization centres: BC Cancer Agency, Ally A, Balasundaram M, Butterfield YS, Carlsen R, Carter C, Chu A, Chuah E, Chun HJ, Coope RJ, Dhalla N, Guin R, Hirst C, Hirst M, Holt RA, Lee D, Li HI, Mayo M, Moore RA, Mungall AJ, Pleasance E, Gordon Robertson A, Schein JE, Shafiei A, Sipahimalani P, Slobodan JR, Stoll D, Tam A, Thiessen N, Varhol RJ, Wye N, Zeng T, Zhao Y, Birol I, Jones SJ, Marra MA; Broad Institute, Cherniack AD, Saksena G, Onofrio RC, Pho NH, Carter SL, Schumacher SE, Tabak B, Hernandez B, Gentry J, Nguyen H, Crenshaw A, Ardlie K, Beroukhim R, Winckler W, Getz G, Gabriel SB, Meyerson M; Brigham & Women’s Hospital & Harvard Medical School, Chin L, Park PJ, Kucherlapati R; University of North Carolina, Chapel Hill, Hoadley KA, Todd Auman J, Fan C, Turman YJ, Shi Y, Li L, Topal MD, He X, Chao HH, Prat A, Silva GO, Iglesia MD, Zhao W, Usary J, Berg JS, Adams M, Brooker J, Wu J, Gulabani A, Bodenheimer T, Hoyle AP, Simons JV, Soloway MG, Mose LE, Jefferys SR, Balu S, Parker JS, Neil Hayes D, Perou CM; University of Southern California/Johns Hopkins, Malik S, Mahurkar S, Shen H, Weisenberger DJ, Triche Jr T, Lai PH, Bootwalla MS, Maglinte DT, Berman BP, Van Den Berg DJ, Baylin SB, Laird PW; Genome data analysis: Baylor College of Medicine, Creighton CJ, Donehower LA; Broad Institute, Getz G, Noble M, Voet D, Saksena G, Gehlenborg N, Dicara D, Zhang J, Zhang H, Wu CJ, Yingchun Liu S, Lawrence MS, Zou L, Sivachenko A, Lin P, Stojanov P, Jing R, Cho J, Sinha R, Park RW, Nazaire MD, Robinson J, Thorvaldsdottir H, Mesirov J, Park PJ, Chin L; Institute for Systems Biology, Reynolds S, Kreisberg RB, Bernard B, Bressler R, Erkkila T, Lin J, Thorsson V, Zhang W, Shmulevich I; Memorial Sloan-Kettering Cancer Center, Ciriello G, Weinhold N, Schultz N, Gao J, Cerami E, Gross B, Jacobsen A, Sinha R, Arman Aksoy B, Antipin Y, Reva B, Shen R, Taylor BS, Ladanyi M, Sander C; Oregon Health & Science University, Anur P, Spellman PT; The University of Texas MD Anderson Cancer Center, Lu Y, Liu W, Verhaak RR, Mills GB, Akbani R, Zhang N, Broom BM, Casasent TD, Wakefield C, Unruh AK, Baggerly K, Coombes K, Weinstein JN; University of California, Santa Cruz/Buck Institute, Haussler D, Benz CC, Stuart JM, Benz SC, Zhu J, Szeto CC, Scott GK, Yau C, Paull EO, Carlin D, Wong C, Sokolov A, Thusberg J, Mooney S, Ng S, Goldstein TC, Ellrott K, Grifford M, Wilks C, Ma S, Craft B; NCI, Yan C, Hu Y, Meerzaman D; Biospecimen core resource: Nationwide Children’s Hospital Biospecimen Core Resource, Gastier-Foster JM, Bowen J, Ramirez NC, Black AD, Xpath Error Unknown Variable Tname RE, White P, Zmuda EJ, Frick J, Lichtenberg TM, Brookens R, George MM, Gerken MA, Harper HA, Leraas KM, Wise LJ, Tabler TR, McAllister C, Barr T, Hart-Kothari M; Tissue source sites: ABS-IUPUI, Tarvin K, Saller C, Sandusky G, Mitchell C; Christiana, Iacocca MV, Brown J, Rabeno B, Czerwinski C, Petrelli N; Cureline, Dolzhansky O, Abramov M, Voronina O, Potapova O; Duke University Medical Center, Marks JR; The Greater Poland Cancer Centre, Suchorska WM, Murawa D, Kycler W, Ibbs M, Korski K, Spychała A, Murawa P, Brzeziński JJ, Perz H, Laźniak R, Teresiak M, Tatka H, Leporowska E, Bogusz-Czerniewicz M, Malicki J, Mackiewicz A, Wiznerowicz M; ILSBio, Van Le X, Kohl B, Viet Tien N, Thorp R, Van Bang N, Sussman H, Duc Phu B, Hajek R, Phi Hung N, Viet The Phuong T, Quyet Thang H, Zaki Khan K; International Genomics Consortium, Penny R, Mallery D, Curley E, Shelton C, Yena P; Mayo Clinic, Ingle JN, Couch FJ, Lingle WL; MSKCC, King TA; MD Anderson Cancer Center, Maria Gonzalez-Angulo A, Mills GB, Dyer MD, Liu S, Meng X, Patangan M; University of California San Francisco, Waldman F, Stöppler H; University of North Carolina, Kimryn Rathmell W, Thorne L, Huang M, Boice L, Hill A; Roswell Park Cancer Institute, Morrison C, Gaudioso C, Bshara W; University of Miami, Daily K, Egea SC, Pegram MD, Gomez-Fernandez C; University of Pittsburgh, Dhir R, Bhargava R, Brufsky A; Walter Reed National Military Medical Center, Shriver CD, Hooke JA, Leigh Campbell J, Mural RJ, Hu H, Somiari S, Larson C, Deyarmin B, Kvecher L, Kovatich AJ; Disease working group, Ellis MJ, King TA, Hu H, Couch FJ, Mural RJ, Stricker T, White K, Olopade O, Ingle JN, Luo C, Chen Y, Marks JR, Waldman F, Wiznerowicz M, Bose R, Chang LW, Beck AH, Maria Gonzalez-Angulo A; Data coordination centre, Pihl T, Jensen M, Sfeir R, Kahn A, Chu A, Kothiyal P, Wang Z, Snyder E, Pontius J, Ayala B, Backus M, Walton J, Baboud J, Berton D, Nicholls M, Srinivasan D, Raman R, Girshik S, Kigonya P, Alonso S, Sanbhadti R, Barletta S, Pot D; Project team: National Cancer Institute, Sheth M, Demchok JA, Mills Shaw KR, Yang L, Eley G, Ferguson ML, Tarnuzzer RW, Zhang J, Dillon LA, Buetow K, Fielding P; National Human Genome Research Institute, Ozenberger BA, Guyer MS, Sofia HJ, Palchik JD. Nature. 2012 Sep 23.

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http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature11412.pdf